Preformulation for tabletting natural mixtures of conjugated estrogens

ABSTRACT

A pharmaceutical preformulation in the form of a solid, free-flowing dry extract of a natural mixture of conjugated equine estrogens, which is particularly suitable use in for solid galenic forms, e.g. tabletting. The conjugated estrogens are available for further galenic processing in a form which assures the chemical stability of the hormones and permits advantageous processing into solid galenic forms, for example a tablet. The invention furthermore relates to a method for producing these preformulations in the form of a dry extract.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of international patent applicationno. PCT/EP02/14104, filed Dec. 12, 2002, designating the United Statesof America, and published in German as WO 03/051337, the entiredisclosure of which is incorporated herein by reference. Priority isclaimed based on European patent application no. EP 01129840.3, filedDec. 14, 2001.

BACKGROUND OF THE INVENTION

The present invention relates to pharmaceutical preformulations in theform of a dry extract of natural mixtures of conjugated equineestrogens, in particular of mixtures of conjugated estrogens obtainedfrom the urine of pregnant mares. Dry extracts as preformulations ofthese natural mixtures of conjugated estrogens suitable for theproduction of solid galenic forms, e.g. for tabletting, are therebyprovided. The invention furthermore relates to a method for theproduction of these preformulations in the form of a dry extract.

Estrogens are used in medicine for hormone replacement therapy. Inparticular, estrogen mixtures are used for the treatment and prophylaxisof the disorders of the climacteric period which occur in women afternatural or artificial menopause. In this case, natural mixtures ofconjugated equine estrogens such as are found in the urine of pregnantmares have proved particularly effective and readily compatible.

The dissolved solids content in the urine of pregnant mares (=pregnantmares' urine, abbreviated hereafter as “PMU”) can naturally vary withinwide ranges, and may generally lie in a range of 40 to 90 g dry matterper liter. In addition to urea and other usual urine contents, phenolicconstituents, e.g. cresols anddihydro-3,4-bis[(3-hydroxyphenyl)methyl]-2(3H)-furanone, known as HPMF,are contained in the solids content of the PMU. The natural mixture ofestrogens contained in the PMU is largely present in conjugated form,e.g. as sulfuric acid semi-ester sodium salt (abbreviated hereafter as“sulfate salt”). The content of conjugated estrogens (abbreviatedhereafter as “CE”), calculated as estrogen sulfate salt and relative todry matter, may be between 0.3 and 1% by weight.

By separating out the undesirable accompanying substances, such as ureaand in particular cresols and HPMF, usually extracts are obtained fromthe PMU which contain the conjugated estrogens from pregnant mares'urine (PMU) in dissolved form (solution extracts). More recent methodsobtain natural mixtures of these conjugated estrogens (CE) bysolid-phase extraction of the mixture of conjugated estrogens frompregnant mares' urine e.g. on RP silica gel (WO 98/08525) or onsemipolar, in particular on non-ionic semipolar, polymeric adsorptionresins (WO 98/08526). With these methods, the undesirable accompanyingsubstances can be separated from the PMU effectively and efficiently andaqueous solution extracts of the CE of good quality can be obtained. Theconcentration of the CE in the solution extract is however subject tocertain unavoidable fluctuations, since the PMU used for obtaining theCE as a natural starting material per se is subject to naturalfluctuations in quality owing to its origin, storage, transport and anypre-processing etc.

In the production of pharmaceutical preparations of natural mixtures ofconjugated equine estrogens from CE-containing solution extracts, aconstant quality and metering strength of the preparation must beensured. The natural fluctuations in the content of conjugated equineestrogens in the solution extracts used for the production ofpharmaceutical preparations which occur as a function of the yield andquality of the starting material therefore have to be compensated for bysuitable measures, in order to provide a material of constant qualityand defined specification for further galenic processing.

There is therefore a need for suitable improved methods for conversionof the CE-containing aqueous solution extracts obtained by working upPMU into a solid galenic preformulation which is as protective of theproduct as possible, which contains the natural mixture of conjugatedequine estrogens as active component in defined form and concentrationand in a homogeneous distribution and then can be used as solidpharmaceutical raw material containing active substance (“dry extract”)in simple manner for further galenic processing into solid forms, suchas for example for tabletting or direct tabletting. The natural mixtureof conjugated equine estrogens must therefore be present in a form whichassures the chemical stability of the hormones, i.e. the conjugatedestrogens contained in the mixtures, and which permits the processing ofthese hormones into a solid galenic form, e.g. a tablet.

SUMMARY OF THE INVENTION

It is thus an object of the present invention to provide a solid,free-flowing pharmaceutical raw material (dry extract) as startingmaterial for the galenic preparation of CE-containing pharmaceuticals insolid form, for example by tabletting or direct tabletting, wherein theraw material provided as starting material for the galenic processingcontains a natural mixture of conjugated equine estrogens obtained frompregnant mares' urine as active component in a defined form, homogenousdistribution and a defined, standardized active-substance content on apharmaceutical support material.

It has now surprisingly been found that aqueous solution extractsobtained by working-up PMU which contain a mixture of natural conjugatedequine estrogens (CE) can be applied in simple manner asactive-substance constituent on to a solid pharmaceutical supportmaterial fluidized in a fluidized bed in a homogenous distribution andwith a defined, standardized concentration, with active substance-coatedparticles of defined form being produced and the active substance, i.e.the natural mixture of conjugated equine estrogens, being present invery stable manner bound in a solid form. This pharmaceuticalpreformulation can be easily processed further galenically as ahigh-quality solid, free-flowing powder and/or granular dry extract, inparticular by tabletting or direct tabletting, to form solidpharmaceutical preparations.

The present invention therefore relates to a pharmaceuticalpreformulation in the form of a solid, free-flowing dry extract fortabletting, characterized by

-   (a) a standardized active-substance content (relative to the main    hormone constituents) of a mixture of natural conjugated equine    estrogens defined per amount of support material, wherein-   (b) the active-substance content is applied by spraying from an    aqueous solution on to a powdered and/or granular pharmaceutical    support material from the group of microcrystalline celluloses or a    mixture of microcrystalline cellulose with lactose and drying.

Conjugated equine estrogens are a mixture of various conjugated forms ofestrogens which are obtained from pregnant mares' urine. The twoprincipal main constituents are sodium estrone sulfate and sodiumequilin sulfate. A third essential constituent is 17-α-dihydroequilinsulfate. In addition, sodium-17-α-estradiol sulfate andsodium-17-β-dihydroequilin sulfate are also of significance. Conjugatedestrogens (CE) usually contain 52.5 to 61.5% by weight sodium estronesulfate, 22.5 to 30.5% by weight sodium equilin sulfate, 13.5 to 19.5%by weight sodium-17-α-dihydroequilin sulfate, 2.5 to 9.5% by weightsodium-17-α-estradiol sulfate and 0.5 to 4% by weightsodium-17-β-dihydroequilin sulfate. The total proportion of sodiumestrone sulfate and sodium equilin sulfate is usually in the range of79.5 to 88% by weight. The total content of free estrogens such asestrone, equilin and 17-α-dihydroequilin is usually no more than 1.3% byweight. The above percentages relate to what is called the “labelledcontent”, as can usually be determined and calculated in accordance withEuropean Pharmacopoeia 2001 or analogously to USP (United StatesPharmacopoeia) by means of gas-chromatographic profiles, compared withreference solutions.

The active-substance content of the hormones contained in the mixture ofnatural conjugated equine estrogens is usually standardized relative tothe main hormone constituents, in which case as a rule it is geared tothe total of the three main constituents estrone, equilin and17-α-dihydroequilin, but occasionally also to the total of these threemain constituents and additionally 17-α-estradiol and17-β-dihydroequilin (in each case conjugated and free hormones).

In advantageous embodiments of the present invention, the pharmaceuticalpreformulation is distinguished in that the active-substance contentcalculated as dry matter (DM) of an extract containing the mixture ofnatural conjugated equine estrogens from pregnant mares' urine (totalhormone content including the free estrogens and other solids) relativeto the amount of the pharmaceutical support material in thepreformulation lies in the range of 0.25 to 0.70 g DM/g supportmaterial, preferably in the range of 0.28 to 0.64 g DM/g supportmaterial.

If the active-substance content (total hormone content including thefree estrogens) of the pharmaceutical preformulation is calculated as amixture of natural equine conjugated estrogens (CE) relative to theamount of the pharmaceutical support material in the preformulation, theactive-substance content lies in the range of 35 to 100 mg CE/g supportmaterial, preferably in the range of 43 to 90 mg CE/g support material.

After drying the pharmaceutical preformulation obtained by spraying theCE-active-substance content from an aqueous solution on to the powderedand/or granular pharmaceutical support material from the group ofmicrocrystalline celluloses or on to a mixture of at least one of thesemicrocrystalline celluloses with lactose, this may, due to the way it isproduced, still contain a small amount of residual moisture. Usually theresidual moisture content in this case lies within the scope of theusual maximum values for the drying processes used. Thus the residualmoisture in the pharmaceutical preformulation is in particular at mostabout 3.0% by weight, preferably at most about 1.0% by weight, relativeto the total preformulation as 100% by weight (total of theactive-substance content calculated as dry matter, the pharmaceuticalsupport material and taking into account the proportion of residualmoisture).

If the active-substance content of the pharmaceutical preformulationaccording to the invention is calculated as total hormone content (totalof all conjugated and free hormones), then the active-substance contentlies in the range of about 35 to 100 mg per 1 g of the pharmaceuticalsupport material, preferably in the range of about 43 to 90 mg per 1 gof the pharmaceutical support material.

Advantageous embodiments of the pharmaceutical preformulation accordingto the invention are distinguished in that the conjugated hormones (ineach case as sodium salt of the sulfate ester), in particular theconjugated main hormones, are contained in the active-substance contentin the following proportions: 52.5 to 61.5% estrone, 22.5 to 30.5%equilin, 13.5 to 19.5% 17-α-dihydroequilin, 2.5 to 9.5% estradiol, 0.5to 4.0% 17-β-dihydroequilin.

Furthermore, in advantageous variants of the pharmaceuticalpreformulation according to the invention the total proportion of freehormones in the preformulation lies in the range of at most about 2 to 3mg per 1 g of the pharmaceutical support material. Preferably theproportion of free hormones in the active-substance content of thepreformulation relative to the total content of hormones (total of allconjugated and free hormones) is below 5% by weight. Depending on theworking-up of the hormone-containing aqueous solution extract used forthe production of the pharmaceutical preformulation according to theinvention, the proportion of free hormones relative to the total hormonecontent may also be considerably lower, e.g. below 2% by weight.

It has surprisingly been demonstrated that by spraying a CE-solutionextract obtained from PMU on to certain pharmaceutical supportmaterials, such as microcrystalline celluloses or mixtures of thesemicrocrystalline celluloses with lactose, by the fluidized-bedtechnique, the conjugated hormones can be homogeneously applied to thesesupport materials and that the solid, free-flowing dry extract obtainedthereby is advantageously suitable for producing solid galenic forms,such as tablets. In particular, the pharmaceutical preformulationsaccording to the invention may be distributed and compressedhomogeneously into a tablet in the form of the dry extract, preferablyinto a matrix tablet, it being possible to achieve desired releaseprofiles. Surprisingly, it was also shown that by selecting thepharmaceutical support material as a function of the solubility in waterof the support material or support material mixture the release rate ofconjugated hormones present in compressed form in a matrix tablet can beadvantageously influenced. In that case, in particular the type andcomposition of the pharmaceutical support material or support materialmixture, e.g. the type and the properties of microcrystalline celluloseand lactose, the particle size and the porosity of the active-substancegranules and the particle-size distribution advantageously influence thequality of the compressibility of the resulting pharmaceuticalpreformulation obtained according to the invention and as a result therelease profile of the conjugated hormones from a matrix tablet producedby means of this pharmaceutical preformulation. Furthermore, in additionto the above-mentioned pharmaceutical support materials or supportmaterial mixtures selected according to the invention, small quantitiesof further conventional tabletting auxiliaries or stabilizers may bepresent in small quantities in the pharmaceutical preformulationaccording to the invention, which makes possible further influencing ofthe release profile of the hormones and their stability in thepharmaceutical preformulation or solid pharmaceutical preparationsproduced therefrom such as tablets, in particular matrix tablets. Suchtabletting auxiliaries are e.g. fillers, disintegrating agents,decomposition promoters or accelerators, dry binding agents, dryingagents or adsorbents, lubricants (e.g. sliding agents, glidants or mouldlubricants). These tabletting auxiliaries which have been named by wayof example, or also further auxiliaries familiar to the person skilledin the art and usually used in tablet production, may be admixed to thepreformulations according to the invention at most in those quantitiesin which they are also intended to be present in the finished matrixtablet.

The successful usability of the preformulation according to theinvention for the production of solid galenic forms of natural mixturesof conjugated equine estrogen, in particular e.g. of tablets orpreferably matrix tablets, is an important partial step in theproduction of the actual solid galenic form for therapeutic orprophylactic administration to patients, and is based, in addition toother factors, also on the type of powdered and/or granularpharmaceutical support materials selected according to the invention,namely in particular pharmaceutical support materials from the group ofmicrocrystalline celluloses and lactose, used optionally in a mixturewith microcrystalline cellulose. If the pharmaceutical support materialin the pharmaceutical preformulation according to the invention is amicrocrystalline cellulose, this may be a single type ofmicrocrystalline cellulose or alternatively a mixture of different typesof microcrystalline celluloses. Another variant of the inventioncontains mixtures of microcrystalline cellulose with lactose which areeach present in powdered and/or granular form. In the variant of thepreformulations according to the invention, in which mixtures of amicrocrystalline cellulose with lactose are present as support material,the mixture ratio thereof may be varied within wide ranges, howeveradvantageously care should be taken that the amount of themicrocrystalline cellulose should not be below 60% by weight, preferablynot below 80% by weight, and the amount of the lactose should not beabove 40% by weight, preferably not above 20% by weight. Advantageousmixture ratios of microcrystalline cellulose to lactose are yielded ifthe weight ratio of microcrystalline cellulose to lactose lies in therange of 8:2 to 6:4, preferably in the range of 7.5:2.5 to 6.5:3.5. Inan embodiment by way of example of the preformulation according to theinvention, the mixture ratio of microcrystalline cellulose to lactose isabout 7:3 as a weight ratio.

Microcrystalline celluloses are commercially available as pharmaceuticalbase material in various forms, e.g. as Avicel® (e.g. from Lehmann &Voss & Co., Hamburg, Germany), in particular as Avicel® types PH 101, PH102, PH 102 SCG or PH 103. The microcrystalline celluloses forpharmaceutical purposes commercially available as Avicel® usually havee.g. the following general specification: water content below 5% byweight (type PH 103: below 3% by weight); ash below 10; refractive index1.55; pH (dispersion) 5.5 to 7.0; average grain sizes for

Type PH 101 PH 102 PH 102 SCG PH 103 50 μm 100 μm 130 μm 50 μm;and a particle size distribution of:

Type PH 101 PH 102 PH 102 SCG PH 103 250 μm <1% <8% <8% <1% 150 μm >23% 75 μm <30% >45% >63% <30%

A further commercially available microcrystalline cellulose forpharmaceutical purposes usable according to the invention is sold underthe trade name Vivapur®, e.g. as type Vivapur® 101 or Vivapur® 12, (e.g.by J. Rettenmaier & Söhne GmbH+Co, Rosenberg, Germany). Vivapur® 101usually has e.g. the following general specification: loss on drying atmost 6% by weight; degree of polymerisation (identity) <350; bulkdensity 0.26 to 0.32 g/ml; grain size distribution: d₁₀: <30 μm, d₅₀: 40to 70 μm, d₉₀: >80 μm; sieve analysis (residue on the air-jetsieve): >250 μm at most 1% by weight, >75 μm at most 30% by weight, >32μm at least 50% by weight; pH 5.0 to 7.0; sulfate ash at most 0.05% byweight. Vivapur® 12 usually has e.g. the following generalspecification: loss on drying at most 6% by weight; bulk density about0.35 g/ml; ramming volume about 1.9 ml/g; average grain size 160 μm;grain size distribution: d₁₀: <30 μm, d₅₀: 40 to 70 μm, d₉₀: >80 μm;sieve analysis (residue on the air-jet sieve): >400 μm at most 1% byweight, >160 μm at most 50% by weight, >50 μm at least 70% by weight.

Lactose is likewise commercially available as a pharmaceutical basematerial as a white, sieved, crystalline, odorless powder which isreadily soluble in water and practically insoluble in ethanol, e.g. asCapsulac® (from Meggle), in particular as Capsulac® 60 or Capsulac® 200.The lactose for pharmaceutical purposes commercially available asCapsulac® 60 usually has the following specification: acid- oralkaline-reacting substances at most 0.4 ml 0.1 n sodium hydroxidesolution; specific rotation 54.4° to 55.9°; water (German Pharmacopoeia)4.5 to 5.5%; loss on drying at most 0.5% by weight; sulfate ash at most0.1% by weight; residue on ignition at most 0.1% by weight; grain sizedistribution (vibratory sieving, 25 g, 10 minutes): <100 μm at most 10%by weight, <630 μm at most 97% by weight. The lactose for pharmaceuticalpurposes commercially available as Capsulac® 200 (type EP D 80) usuallyhas the following specification: acid- or alkaline-reacting substancesat most 0.19 ml 0.1 n sodium hydroxide solution; specific rotation55.4°; total water 5.39% by weight; loss on drying 0.17% by weight;sulfate ash 0.04% by weight; residue on ignition 0.04% by weight; grainsize distribution (air-jet sieving, 10 g, 2 minutes): <32 μm 45 to 75%by weight, <100 μm at least 90% by weight.

In advantageous embodiments, the preformulations according to theinvention may be characterized by further parameters, such as theparticle-size distribution, the mean or average particle size, theporosity of the particles, the mean apparent density (bulk density)and/or mean bulk volume.

Advantageous pharmaceutical preformulations according to the inventionhave e.g. a mean bulk volume in the range of 1.8 to 3.0 ml/g. The meanapparent density (bulk density) of the pharmaceutical preformulationaccording to the invention lies e.g. in the range of 0.3 to 0.6 g/ml. Inone alternative, the pharmaceutical preformulation according to theinvention is distinguished in that the preformulation has aparticle-size distribution characterized by sieve analysis as apercentage throughput total as a function of the sieve mesh size of 100%by weight of the particles for a mesh size of 500 μm, of at least 98% byweight of the particles for a mesh size of 250 μm, of about 65 to 99.5%by weight of the particles for a mesh size of 160 μm, of about 35 to 87%by weight of the particles for a mesh size of 125 μm, and fines of lessthan 23% by weight for a mesh size of 63 μm, in each case relative tothe overall total of the sieve fractions as 100% by weight.Alternatively, the pharmaceutical preformulation according to theinvention is distinguished in that the preformulation has aparticle-size distribution characterized by sieve analysis as a functionof the sieve mesh size of approximately 0.15 to at most 2% by weight ofthe particles larger than a mesh size of 250 μm, of approximately 3 to31% by weight of the particles larger than a mesh size of 160 μm, ofapproximately 8 to 36% by weight of the particles larger than a meshsize of 125 μm and fines of the particles of about 3 to at most 23% byweight for a mesh size of 63 μm, in each case relative to the overalltotal of the sieve fractions as 100% by weight. The mean (average)particle size of the pharmaceutical preformulation according to theinvention advantageously lies in the range of 50 to 250 μm, preferablyin the range of 75 to 150 μm.

The present invention furthermore also relates to a method for theproduction of the dry extracts of natural mixtures of conjugated equineestrogens according to the invention as described above, in particularof mixtures of conjugated estrogens obtained from pregnant mares' urine,wherein pharmaceutical preformulations of natural mixtures of conjugatedestrogens are provided by these dry extracts, which preformulations aresuitable for the production of solid galenic forms, e.g. for theproduction of tablets and in particular also if desired also for directtabletting. The method of the invention for the production of thepharmaceutical preformulation according to the invention in the form ofa solid, free-flowing dry extract of the type defined above fortabletting is distinguished in that an aqueous solution which contains amixture of natural conjugated equine estrogens as active substance issprayed in an amount which corresponds to the defined standardized(relative to the main hormone constituents) active-substance contentdesired in the pharmaceutical preformulation on to a powdered and/orgranular pharmaceutical support material, fluidized in a fluidized-bedapparatus, which is selected from the group of microcrystallinecelluloses or a mixture of microcrystalline cellulose with lactose, andthe resulting particles containing active substance are dried.

The microcrystalline cellulose types and lactose types usable in themethod have already been described further above in conjunction with thepharmaceutical preformulations according to the invention.

For the method according to the invention, a CE-containing aqueoussolution extract obtained from PMU of any origin can be used in a widerange of varying CE concentration, which can be obtained by the work-upmethod for the PMU described further above in relation to the prior art,in particular by the method described in WO 98/08526 or similar methodsusing semipolar, preferably non-ionic semipolar adsorption resins.Depending on the concentration of the CE and the accompanying substancespossibly remaining in these extracts, these aqueous extracts may beconcentrated by further removal of solvent or be set to desiredactive-substance contents for use in the method of the present inventionby the addition of further water or of water-miscible organic solventssuch as lower aliphatic alcohols.

In one variant of the method according to the invention, the aqueoussolution containing active substance which is used may thus, in additionto the water, also contain other water-miscible organic solvents, inparticular one or more lower aliphatic alcohols, as additional solvent.Suitable lower aliphatic alcohols are in particular those having one tofour carbon atoms, for example methanol, ethanol, isopropanol orn-butanol. Methanol, ethanol or isopropanol are preferred. The organicsolvents, in particular the alcohols, may also be added to the aqueoussolution in a mixture with one another as additional solvent. The amountof the water-miscible organic solvent proportion, in particular thealcohol proportion, in the aqueous solution may lie in the rangesdescribed as suitable in WO 98/08526. Other possibly suitablewater-miscible solvents such as ketones or water-soluble ethers arelikewise described in WO 98/08526.

Preferably in the method according to the invention aqueous solutionscontaining active substance, i.e. CE extract solutions or concentrates,are used which are an aqueous solution largely freed of organic solventand suitable for galenic further processing, i.e. an essentially aqueoussolution, of the CE or a concentrate of the CE largely freed of organicsolvent. Purely aqueous solutions or concentrates of the natural mixtureof conjugated estrogens are very much preferred in this case.

Advantageous variant embodiments of the present method according to theinvention are distinguished in that the aqueous solution used has anactive-substance content calculated as dry matter of the mixture ofnatural equine conjugated estrogens (total hormone content including thefree estrogens and other solids) in the range of approximately 3.5 to20% by weight relative to the aqueous solution as 100% by weight.Preferably the active-substance content in the aqueous solutioncalculated as dry matter of the natural mixture of conjugated equineestrogens lies in the range from approximately 3.5 to 14.5% by weight,relative to the aqueous solution as 100% by weight. If theactive-substance content of the aqueous solution used according to theinvention in the method is calculated as total hormone content(including the free estrogens), the aqueous solution used has anactive-substance content in the range of 10 to 100 mg per 1 g of theaqueous solution, preferably in the range of 10 to 40 mg per 1 g of theaqueous solution.

If in the method according to the invention a concentrate is used asaqueous solution, this will advantageously have an active-substancecontent calculated as dry matter of the mixture of natural conjugatedequine estrogens (total hormone content including the free estrogens andother solids) in the range of more than 20% by weight, relative to theconcentrate as 100% by weight. If the active-substance content of theaqueous concentrate used according to the invention in the method iscalculated as total hormone content (including the free estrogens) ofthe mixture of natural equine conjugated estrogens (CE), the concentrateused advantageously has an active-substance content of greater than 40mg per 1 g of the concentrate (100% by weight.

Advantageously, aqueous solutions in which the total hormone content(including the free estrogens) relative to the dry matter contained inthe aqueous solution as 100% by weight lies in the range of 18 to 31% byweight are used in the method according to the invention.

The method according to the invention for the production of the dryextracts or preformulations of natural mixtures of conjugated estrogensaccording to the invention, in particular of mixtures of conjugatedestrogens obtained from pregnant mares' urine, can be carried out in anyconventional fluidized-bed drying apparatus, in particular those for usein the pharmaceutical industry. Suitable fluidized-bed apparatus aree.g. the fluidized-bed apparatus “Strea I”. In the method according tothe invention, the powdered or granular pharmaceutical support material,e.g. the microcrystalline cellulose or a mixture of microcrystallinecellulose with lactose, is placed in the fluidized-bed apparatus in apre-calculated production amount and fluidized by means of an aircurrent. Then an aqueous solution containing a natural mixture ofconjugated estrogens as active substance in an amount which correspondsto the active-substance content desired in the preformulation is sprayedon to the support material and the resulting particles containing activesubstance are dried.

The method in this case may be performed both continuously anddiscontinuously in batch operation and in addition to the type andamount of the support material used or in addition to the type, amountand the active-substance content of the aqueous solution used, mayfurthermore be controlled via method parameters familiar to the personskilled in the art in the field of fluidized beds, such as incoming andoutgoing air temperatures, quantity of the air current supplied andremoved, the spraying rate of the aqueous solution and also, in the caseof a continuous procedure, by the rate of the introduction of solids anddischarge of product and/or the dwell time of the product in thefluidized-bed apparatus.

In one advantageous variant of the method according to the invention,e.g. the temperature, regulated using the exhaust air temperature, ofthe preformulation product fluidized in the fluidized-bed apparatus liesin the range of 25 to 60° C., preferably in the range of 45 to 55° C. Inan example of embodiment of the method according to the invention, thetemperature, regulated using the exhaust air temperature, of thepreformulation product fluidized in the fluidized-bed apparatus isapproximately 45 to 55° C.

In another advantageous variant of the method according to theinvention, e.g. the process moisture regulated via the relative humidityof the exhaust air in the fluidized-bed apparatus lies in the range of50 to 80% r.h. (r.h.=relative humidity).

In yet another advantageous variant of the method according to theinvention, e.g. the aqueous solution containing active substance whichis used is sprayed at a spraying rate of 20 to 50 g/min on to thepowdered and/or granular pharmaceutical support material fluidized inthe fluidized-bed apparatus.

In the method according to the invention for producing the dry extractsor preformulations of natural mixtures of conjugated estrogens accordingto the invention, in particular of mixtures of conjugated estrogensobtained from pregnant mares' urine, in advantageous variant embodimentspowdered and/or granular support materials are used which arecharacterized by certain particle properties and thus can be used forthe deliberate control of the particle properties of the dry-extract orpreformulation product. Suitable parameters for the particle propertiesof the powdered or granular support materials used, just like for thecharacterisation of the dry-extract or preformulation products producedon this basis are e.g. the particle-size distribution, the mean oraverage particle size, the porosity of the particles or the meanapparent density and also further parameters deemed advantageous by theperson skilled in the art in the specific case. A few advantageousranges of these particle parameters will be given below for orientationpurposes.

In an advantageous variant of the method according to the invention, apowdered and/or granular pharmaceutical support material, in particulara microcrystalline cellulose, is used which has a particle-sizedistribution characterized by sieve analysis as a percentage throughputtotal as a function of the sieve mesh size of 100% by weight of theparticles for a mesh size of 500 μm, of at least 99% by weight of theparticles for a mesh size of 250 μm, of about 85 to 95% by weight of theparticles for a mesh size of 160 μm, of about 70 to 80% by weight of theparticles for a mesh size of 125 μm, and fines of up to about 50% byweight for a mesh size of 63 μm, in each case relative to the overalltotal of the sieve fractions as 100% by weight. Particularlyadvantageous powdered and/or granular pharmaceutical support materialsused in the method according to the invention, in particular themicrocrystalline cellulose, in this case have a mean (average) particlesize in the range of 50 to 130 μm. The powdered and/or granularpharmaceutical support material used in the method according to theinvention, in particular the microcrystalline cellulose, has e.g. anapparent density (bulk density) in the range of approximately 25 to 35g/ml. Furthermore, the powdered and/or granular pharmaceutical supportmaterials used in the method according to the invention, in particularthe microcrystalline cellulose, are characterized in that the watercontent (loss on drying) is at most about 6% by weight.

According to the method of the invention, advantageously a startingmaterial serving for the production of pharmaceuticals which contain thenatural mixture of conjugated estrogens from PMU as active component isprovided, which is advantageously suited as dry extract orpreformulation of excellent quality for further processing by directtabletting.

The method according to the invention and the preformulation accordingto the invention have a number of advantages in particular also comparedwith other procedures. CE-containing aqueous extracts with low hormoneconcentration can be processed. In contrast to what is observed withconventional spray-drying of such CE-containing extracts, in the methodaccording to the invention in a fluidized bed undesirable attachments,e.g. to the nozzles, are not observed. The thermal loading of thevaluable hormone constituents of the aqueous extracts used is very lowin the fluidized bed in the method according to the invention. Stickyproperties, e.g. agglomeration, of the CE-containing aqueous extractmake themselves felt less than with other drying methods such assingle-pot technology. Compared with operating methods in vacuum dryersetc., the method according to the invention is a continuouslyperformable method which in addition—both with continuous and withdiscontinuous operation—permits the application of large quantities ofliquid, even without over-wetting. In the method according to theinvention, a broad range of extracts both with regard to the hormoneconcentration and to the concentration of accompanying substances can beprocessed. Because of this, the method is able to solve very well theproblems which have to be overcome due to the natural fluctuations ofthe PMU-starting material in full-scale practice. It was demonstratedthat the conjugated hormones can be applied homogeneously to the supportmaterials by spraying a hormone concentrate using fluidized-bedtechnology on to support materials used according to the invention, suchas microcrystalline cellulose or optionally mixtures of microcrystallinecellulose with lactose. The preformulations produced in accordance withthe method according to the invention in the form of solid, free-flowingdry extracts are very stable powdered or particulate hormone-containingproducts, which can be homogeneously distributed in matrix tablets andcompressed surprisingly well. Thus matrix tablets with a desired releaseprofile can be produced from the pharmaceutical preformulationsaccording to the invention in simple manner.

The following examples are intended to illustrate the invention infurther detail without limiting its scope.

EXAMPLES Example 1

Drying and Production of a Preformulation with Hormone-Containing ActiveSubstance in a Fluidized-Bed Apparatus, and Hormone Content

A series of tests were carried out with the aim of developing ahormone-containing active substance by drying the hormones from urineconcentrate from pregnant mares. The conjugated hormones in this casehad to be put into a form which guarantees the chemical stability of thehormones and permits processing of the hormones into a tablet. A urineconcentrate (concentrated aqueous solution of pregnant mares' urine=PMU)from a collecting campaign in Asia was used, which was characterized byits amount of dry matter and hormone concentration. The urineconcentrate was worked up before use in accordance with the method of WO98/08526, in order to separate off undesirable accompanying substancessuch as urea, HPMF and cresols.

In the tests, it was demonstrated that the conjugated hormones could beapplied homogeneously to the auxiliaries by spraying the hormoneconcentrate on to support materials such as microcrystalline celluloseor mixtures of microcrystalline cellulose with lactose usingfluidized-bed technology.

A urine concentrate provided from a collecting campaign was sprayed onto microcrystalline cellulose or on to a mixture of microcrystallinecellulose and lactose and the hormones were thereby applied to thesupport or the mixture of support materials. This process was carriedout in a fluidized-bed granulator. The particle size and porosity of theactive-substance granules were regulated by the incoming and exhaust airtemperatures and the spraying rate. The product temperature (regulatedusing the exhaust air temperature), which was set in the range of 25 to55° C., and the process humidity (regulated via relative exhaust airhumidity), which was set in the range of 50 to 80% relative airhumidity, served as parameters for the process. The spraying rate wasselected accordingly in order to maintain the aforementioned ranges.

In these tests, a fluidized-bed apparatus (Strea 1) was used for theproduction of dry extracts of natural mixtures of conjugated estrogens,with which about 1 kg dry extract per batch can be produced. The aqueoussolution extract containing a natural mixture of conjugated estrogenswas introduced into the fluidized-bed apparatus using the top-spraymethod. The further industrial equipment comprised:

-   -   Sartorius balance/6.2 kg/type LC6200S-OD2,    -   tubing pump Masterflex 07523-27 with pump head 7518-10,    -   moisture measuring apparatus of the type HR 73 from Mettler        Toledo.

The tests in the fluidized-bed apparatus were carried out with aqueoussolution extracts containing a natural mixture of conjugated estrogenswhich came from a collecting campaign in Asia which was worked up inaccordance with the method described in WO 98/08526, thehormone-containing aqueous extracts having the following hormonecontents:

-   Test 1: DM=9.2% by weight-   Test 2: DM=15.9% by weight-   Test 3: DM=19.3% by weight-   Test 4: DM=9.2% by weight    In further tests, CE-containing aqueous solution extracts with    DM=11.8% by weight (Test 5) or DM=9.9% by weight (Test 6) were used.    The aqueous solution extracts all had a crystalline or oily deposit,    which impaired homogeneous processing, but not substantially. The    aqueous solution extracts had only a relatively low hormone content,    which is why the dry extracts were set to a theoretical desired    content of 45 mg conjugated estrogens per g dry extract.

There were used as support materials for the natural mixture ofconjugated estrogens:

-   -   Avicel PH 102,    -   Capsulac 60.        Performance of the Tests        Production of a dry extract with a content of 45 mg conjugated        estrogens per g dry extract for receiving solutions of 570 to        680 g of the support material.

Test 1: Extract used: 4023.1 g; DM = 9.2% by weight; Density: 1.0365g/l; CE = 12.14 g/l Receiving solution: 677.0 g Avicel PH 102 Sprayingrate: 40-50 g/min (approximate mean value) Relative exhaust airhumidity: 70-80% Exhaust air temperature: 32-34° C.

Test 2: Extract used: 2400.0 g; DM = 15.9% by weight; Density: 1.0662g/l; CE = 20.86 g/l Receiving solution: 661.9 g Avicel PH 102 Sprayingrate: 40-50 g/min (approximate mean value) Relative exhaust airhumidity: 70-80% Exhaust air temperature: 32-34° C.

Test 3: Extract used: 1904.6 g; DM = 19.3% by weight; Density: 1.0662g/l; CE = 20.86 g/l Receiving solution: 574.8 g Avicel PH 102 Sprayingrate: 40-50 g/min (approximate mean value) Relative exhaust airhumidity: 70-80% Exhaust air temperature: 32-34° C.all three tests took place without problems. The spraying times for Test1 were 83 minutes, for Test 2 46 minutes and for Test 3 35 minutes.

Test 4: Extract used: 4023.1 g; DM = 9.2% by weight; Density: 1.0365g/l; CE = 12.14 g/l Receiving solution: 677.0 g Avicel PH 102 Sprayingrate: 40-50 g/min (approximate mean value) Relative exhaust airhumidity: 50-60% Exhaust air temperature: 35-40° C.

This test is a repetition of Test 1, which is intended to check whethera finer dry extract can be produced by reducing the spraying rate. Thedry extract in sieve analyses proved to be finer than the dry extractobtained in Test 1 (see summary of the results of the tests).

Further tests were carried out using analogous procedures to Tests 1 to3 with Avicel PH 102 (Test 5) or with mixtures of Avicel PH 102 andCapsulac 60 (weight ratio 7:3; Test 6).

Test Results

Detailed results on the hormone content in Tests 1 to 4 are compiled inTables I to IV.

In principle it was discovered that, for a receiving solution of 570 gto 680 g Avicel PH 102 as support material, continuous and rapidapplication of the extract is possible (Tests 1 to 3). For the amountsof extract used, which varied from 1900 to 4023 g, the spraying timesfor these tests were between 35 and 83 minutes. This yielded appliedamounts of 0.55 g to 0.64 g solids from the extract per g Avicel (meanvalue: 0.59 g).

In order in a further test (Test 5) to maintain the preset desiredcontent of 45 mg conjugated estrogens per g dry extract or to determinelimits for maximum quantities of active substance which can be applied,in this test the receiving solution of Avicel PH 102 was reduced to342.5 g, compared with the previous Tests 1 to 4, i.e. a reduction ofalmost 50%. 4640 g extract was to be applied. In this case, for up toabout 1600 g extract sprayed on no problems occurred, since up to thisamount as in the preceding Tests 1 to 4 again there was an appliedamount of 0.56 g solids from the extract per g Avicel. For about 2000 gextract sprayed on, an applied amount of 0.68 g was yielded, and forabout 2500 g an amount of 0.86 g solids from the extract per g Avicel.Up to this applied amount, the extract could be sprayed on largelywithout problems. Thereafter, the spraying rate was greatly reduced,since from this amount onwards the solids from the extract exceed theamount of the support material and the product exhibits a tendency tostick from this point onwards. The process was then only operated at arelative humidity of <25%, since the exhaust-air filters clogged up; theamount of air was no longer sufficient to maintain the fluidized bed.The pure spraying time was more than 5 hours.

In summary, it can therefore be said that an application of up to 0.6 gsolids from the extract per g Avicel the entire extract should beprocessed. The upper limit of quantities of extract which Avicel PH 102can take without being impaired lies at about 0.86 g application ofsolids from the extract. Thereafter, it is necessary to reduce the sprayapplication and to adapt the remaining parameters accordingly.

Test 4 is a repetition of Test 1. Here, a finer trituration was producedby changing the parameters (lower spraying rate and hence higher exhaustair temperature and lower exhaust air humidity).

In the additional Test 6, as in Test 4, a reduction in the receivingsolution was effected, in order to be able to set to 45 mg conjugatedestrogens per g trituration (reduction>60% compared with Test 1 and Test2).

Additionally, lactose was used in this case (ratio of Avicel tolactose=7 to 3). In this test, from an applied quantity of 0.6 g solidsfrom the extract per gram of Avicel/lactose mixture onwards, it wasnecessary to lower the spraying rate from 20 g/min to <9 g/min (at V-140the limit was at 0.86 g solids). The amount of extract sprayed on atthis moment was about 40% by weight (<1600 g). From about 1800 gonwards, here too, as already observed in Test 4, there was a tendencyto stick. The test was discontinued after application of 70% amount ofextract, since it was not possible to reduce the spraying rate further(<9 g/min) due to the apparatus.

TABLE I Hormone content for Test 1 Total estrogens Free estrogensSolution Dry Solution Dry extract extract extract extract Estrogens[mg/g] [%]¹⁾ [mg/g] [%]¹⁾ [mg/g] [%]²⁾ [mg/g] [%]²⁾ 17-α-estradiol 0.4554.34 1.856 4.31 0.047 0.196 17-β-estradiol 0.646 6.17 2.631 6.12 0.0820.344 17-α-DH-equilin 1.270 12.12 5.160 11.99 0.098 0.94 0.405 0.9417-β-DH-equilin 0.322 3.07 1.323 3.08 0.019 0.077 17-α-DH-equilenin0.057 0.54 0.229 0.53 0.007 0.021 17-β-DH-equilenin 0.031 0.30 0.2150.50 0.000 0.000 Estrone 6.193 59.12 25.371 58.97 0.247 2.36 1.015 2.36Equilin 2.236 21.34 9.312 21.64 0.057 0.54 0.229 0.53δ-8,9-dehydroestrone 0.293 2.80 1.223 2.84 0.022 0.076 Equilenin 0.1241.18 0.515 1.20 0.000 0.000 Total hormone content 11.627 47.835 0.5792.363 Total main hormones³⁾ 10.476 43.022 0.468 1.922 ¹⁾relative to17-α-estradiol, 17-α-DH-equilin, 17-β-DH-equilin, estrone and equilin²⁾relative to total of 17-α-estradiol, 17-α-DH-equilin, 17-β-DH-equilin,estrone and equilin from total estrogens ³⁾total of the hormones17-α-estradiol, 17-α-DH-equilin, 17-β-DH-equilin, estrone and equilin

TABLE II Hormone balance for Test 2 Total estrogens Free estrogensSolution Dry Solution Dry extract extract extract extract Estrogens[mg/g] [%]¹⁾ [mg/g] [%]¹⁾ [mg/g] [%]²⁾ [mg/g] [%]²⁾ 17-α-estradiol 0.8264.46 2.085 4.49 0.087 0.223 17-β-estradiol 1.220 6.58 3.074 6.62 0.1630.417 17-α-DH-equilin 2.302 12.42 5.824 12.54 0.177 0.96 0.437 0.9417-β-DH-equilin 0.634 3.42 1.506 3.24 0.036 0.087 17-α-DH-equilenin0.124 0.57 0.298 0.64 0.012 0.030 17-β-DH-equilenin 0.103 0.56 0.2420.52 0.000 0.000 Estrone 10.835 58.47 27.056 58.28 0.423 2.28 1.056 2.27Equilin 3.934 21.23 9.957 21.45 0.092 0.50 0.223 0.50δ-8,9-dehydroestrone 0.529 2.85 1.348 2.90 0.016 0.079 Equilenin 0.2201.19 0.543 1.17 0.000 0.000 Total hormone content 20.727 51.933 1.0062.562 Total main hormones³⁾ 18.531 46.428 0.815 2.036 ¹⁾relative to17-α-estradiol, 17-α-DH-equilin, 17-β-DH-equilin, estrone and equilin²⁾relative to total of 17-α-estradiol, 17-α-DH-equilin, 17-β-DH-equilin,estrone and equilin from total estrogens ³⁾total of the hormones17-α-estradiol, 17-α-DH-equilin, 17-β-DH-equilin, estrone and equilin

TABLE III Hormone content for Test 3 Total estrogens Free estrogensSolution Dry Solution Dry extract extract extract extract Estrogens[mg/g] [%]¹⁾ [mg/g] [%]¹⁾ [mg/g] [%]²⁾ [mg/g] [%]²⁾ 17-α-estradiol 1.0034.64 2.208 4.57 0.102 0.227 17-β-estradiol 1.402 6.49 3.072 6.36 0.1660.365 17-α-DH-equilin 2.678 12.40 5.984 12.39 0.207 0.96 0.463 0.9617-β-DH-equilin 0.633 2.93 1.432 2.96 0.038 0.091 17-α-DH-equilenin0.118 0.55 0.232 0.48 0.021 0.031 17-β-DH-equilenin 0.045 0.21 0.0570.12 0.000 0.000 Estrone 12.713 58.87 28.105 58.18 0.492 2.28 1.083 2.24Equilin 4.569 21.16 10.582 21.90 0.107 0.50 0.241 0.50δ-8,9-dehydroestrone 0.539 2.50 1.265 2.62 0.021 0.113 Equilenin 0.2221.03 0.492 1.02 0.000 0.000 Total hormone content 23.922 53.429 1.1542.614 Total main hormones³⁾ 21.596 48.311 0.946 2.105 ¹⁾relative to17-α-estradiol, 17-α-DH-equilin, 17-β-DH-equilin, estrone and equilin²⁾relative to total of 17-α-estradiol, 17-α-DH-equilin, 17-β-DH-equilin,estrone and equilin from total estrogens ³⁾total of the hormones17-α-estradiol, 17-α-DH-equilin, 17-β-DH-equilin, estrone and equilin

TABLE IV Hormone content for Test 4 Total estrogens Free estrogensSolution Dry Solution Dry extract extract extract extract Estrogens[mg/g] [%]¹⁾ [mg/g]¹⁾ [%] [mg/g] [%]²⁾ [mg/g] [%]²⁾ 17-α-estradiol 0.6464.56 2.284 4.56 0.057 0.201 17-β-estradiol 1.093 7.71 3.798 7.58 0.1510.531 17-α-DH-equilin 1.876 13.23 6.367 12.71 0.134 0.94 0.484 0.9717-β-DH-equilin 0.523 3.69 1.768 3.53 0.018 0.109 17-α-DH-equilenin0.070 0.49 0.274 0.55 0.008 0.030 17-β-DH-equilenin 0.000 0.00 0.1030.21 0.000 0.000 Estrone 8.022 56.57 28.947 57.77 0.282 1.99 1.038 2.07Equilin 3.114 21.96 10.743 21.44 0.068 0.50 0.229 0.46δ-8,9-dehydroestrone 0.381 2.69 1.339 2.67 0.022 0.083 Equilenin 0.1190.84 0.543 1.08 0.000 0.000 Total hormone content 15.844 56.166 0.7402.705 Total main hormones³⁾ 14.181 50.109 2.057 ¹⁾relative to17-α-estradiol, 17-α-DH-equilin, 17-β-DH-equilin, estrone and equilin²⁾relative to total of 17-α-estradiol, 17-α-DH-equilin, 17-β-DH-equilin,estrone and equilin from total estrogens ³⁾total of the hormones17-α-estradiol, 17-α-DH-equilin, 17-β-DH-equilin, estrone and equilinEvaluation of the Test Results

The production of a dry extract in the fluidized-bed apparatus, evenwith support materials of different grain-size distribution, is notproblematic. The yield determined for all tests was between 90 and 95%.The hormone distribution, relative to 17-α-DH-equilin, estrone andequilin, is constant in the extract and in the trituration. The dryingprocess therefore has no influence on the stability of the hormones. Theresidual moisture content was between 3 and 6% r.h.

As the tests show, it is possible to process large quantities ofhormone-containing extract of 2 to 4 kg within a short time, i.e. toapply it to support materials and dry it accordingly. The maximumapplied amounts determined (g solids from the extract per g supportmaterial, e.g. Avicel) which can be applied to the selected supportmaterial without process problems should be emphasized as beingparticularly important. In this case it was established that when e.g.Avicel is used as support material an application of up to about 0.6 gactive-substance dry matter from the hormone-containing aqueous solutionextract per g Avicel is completely without problems (Tests 1, 2 and 3 ofExample 1).

Example 2

Production of Dry Extracts Using Aqueous Hormone Extract Solutions withVarying Hormone Content

Further spraying tests were carried out to apply an aqueous solutionextract, containing natural mixtures of equine conjugated estrogens invarious concentrations, on a pharmaceutical support material selectedfrom the group of microcrystalline celluloses. The spraying tests werecarried out analogously to Example 1 in a fluidized-bed sprayingapparatus with 6 different aqueous solution extracts A to F. Theproperties of the aqueous solution extracts A to F used (activesubstance solutions) and the process parameters used in each case can beseen from Table V. Further properties of the pharmaceuticalpreformulations obtained in the form of a solid, free-flowing dryextract are given in Table VI.

The pharmaceutical preformulations obtained in the form of a solid,free-flowing dry extract were then subjected to sieve analysis. Thesieve analysis was carried out with a Retsch sieving machine under thefollowing conditions: 5 min. sieving time, pulse time 3 s, oscillationamplitude 1.50 mm, amount of sample approx. 20 g each time. Sieves witha mesh size of from 1000 μm onwards were used. The results of the sieveanalyses are reproduced in Table VII.

TABLE V Production of dry extract fractions, containing natural mixturesof equine conjugated estrogens, tests in a fluidized-bed spray dryerActive substance solutions A B DM [%] 3.5 7.4 CE [mg/g]: 10.726 17.655CE/DM [%] 30.65 23.9 “TEF” Ch. B.: V-A-1 V-A-2 V-A-3 V-B-1 V-B-2 V-B-3Batch [g]: 2300.00 2300.00 986.56 2295.08 2295.08 2295.08 Conc. extractsoln. [g] 18227.0 18227.0 8278.0 11049.0 11049.0 11049.0 Product temp.[° C.] 45-50 60 45-50 45-50 45-50 45-50 Incoming air temp. 117-121114-121 112-120  91-119 100-119 118-121 [° C.] Exhaust air temp. [° C.]43-45 50-57 42-43 42-47 39-47 39-48 Exhaust air humidity 23-36 14-1727-31 21-29 19-29 22-35 [% r.h.] Spraying rate [g/min] 34-40 20-30 21-3430-39 30-46 37-43 Amount of air [m³/h]  80-100  80-100 70-85  80-100 80-100  80-100 Spraying time [h:m] 07:58 12:17 04:25 02:05 04:50 04:43with process interrupted [Y/N] Y Y N Y N N Residual moisture [%] 2.7 3.22.7 2.1 2.5 2.7 Active substance solutions C D E F DM [%] 12.7 14.5 6.613.6 CE [mg/g]: 33.451 26.274 16.229 38.224 CE/DM [%] 26.34 18.12 24.5928.11 “TEF” Ch. B.: V-C-1 V-C-2 V-D-1 V-D-2 V-E V-F Batch [g]: 2295.082166.23 2265.40 2265.40 2321.61 2335.91 Conc. extract soln. [g] 5833.25504.4 7760.0 7760.0 12224.0 5500.0 Product temp. [° C.] 45-50 45-50 5545-50 45-50 46-50 Incoming air temp. 102-121 106-120  94-117  86-118 96-120  87-116 [° C.] Exhaust air temp. [° C.] 38-46 43-45 50-53 44-4643-46 45-50 Exhaust air humidity 21-36 25-31 17-19 19-29 24-32 28-36 [%r.h.] Spraying rate [g/min] 36-45 30-42 40-52 27-37 32-36 30 Amount ofair [m³/h] 80-90 80-95 110-170  80-130  80-100 80-100 Spraying time[h:m] 02:40 02:30 01:05 04:18 06:03 03:25 with process interrupted [Y/N]N N Y Y Y N Residual moisture [%] 2.7 2.6 2.5 2.5 2.5 2.9

TABLE VI Properties according to Example 2 of resulting pharmaceuticalpreformulations which contain a natural mixture of conjugated equineestrogens as solid, free-flowing dry extract fraction. g dry matter/ mgCE DM [%] 1 g support content per g Bulk Test CE [mg/g] material supportvolume density No. CE/DM [%] (Vivapur 101) material [ml/g] [g/ml] V-A-13.5 277.3 85 2.36 0.42 V-A-2 10.726 2.12 0.47 V-A-3 30.65 293.6 90 2.160.46 V-B-1 7.4 355.6 85 2.48 0.4 V-B-2 17.655 2.5 0.4 V-B-3 23.9 2.680.37 V-C-1 12.7 322.8 85 2.84 0.35 33.451 V-C-2 26.34 322.7 2.44 0.41V-D-1 14.5 496.7 90 2.28 0.44 26.274 V-D-2 18.12 2.12 0.47 V-E 6.6 347.590 2.28 0.44 16.229 24.59 V-F 13.6 320.2 90 2.4 0.42 38.224 28.11

TABLE VII Sieve analyses in accordance with Example 2 of resultingpharmaceutical preformulations in the form of solid, free-flowing dryextracts. V-A-1 V-B-1 V-A-2 V-B-2 V-C-1 Avicel Vivapur Mesh size V-A-3V-B-3 V-C-2 V-E V-F PH 102 101 (μm) TT (%) SR (%) TT (%) SR (%) TT (%)SR (%) TT (%) SR (%) TT (%) SR (%) TT (%) SR (%) TT (%) SR (%) 1000 1000 100 0 100 0 100 0 100 0 100 0 100 0 100 0 100 0 100 0 100 0 100 0 500100 0 100 0 100 0 100 0 100 0 100 0 100 0 100 0 100 0 100 0 100 0 100 0250 99.59 0.41 99.17 0.83 99.20 0.80 99.39 0.61 98.33 1.67 99.48 0.52100 0 99.75 0.25 99.17 0.83 99.81 0.19 99.85 0.15 98.33 1.67 160 92.886.71 88.88 10.28 81.55 17.66 83.09 16.30 86.30 12.02 88.70 10.78 100 096.44 3.31 81.00 18.17 95.66 4.15 95.54 4.32 67.32 31.01 125 71.77 21.1166.31 22.58 57.14 24.40 47.53 35.56 70.83 15.47 76.84 11.87 99.65 0.3586.71 9.73 54.26 26.74 86.78 8.88 78.70 16.84 37.94 29.98  63 9.82 61.9512.68 53.62 8.85 48.29 6.72 40.80 15.37 55.45 43.73 33.11 59.96 39.6921.06 65.65 6.57 47.69 22.53 64.25 13.97 64.73 3.93 33.42 Fines 9.8212.68 8.85 6.72 15.37 43.73 59.96 21.06 6.57 22.53 13.97 3.93 1) TT =throughput total 2) SR = sieve residue

Example 3

Orienting Tabletting Tests

In order to test the galenic further processing ability of the dryextracts or preformulations produced in Example 1 by fluidized-bedtechnology, the dry extracts or preformulations were mixed with furthertabletting auxiliaries and compressed to form matrix tablets. It wasdemonstrated that the mixtures could be homogeneously distributed in amatrix tablet and compressed. Surprisingly, it was demonstrated that byselecting the support material and the further tabletting auxiliaries asa function of the solubility of the support material andtabletting-auxiliary mixture in water the release rate of the conjugatedhormones compressed in the matrix tablets can be decisively influenced,and that thus desired, preset release profiles can be set. Also thecomposition of the support material used as support for the conjugatedestrogens, e.g. of the mixture of microcrystalline cellulose withlactose, the particle size and the porosity of the active-substancegranules, and also the particle-size distribution influence the qualityof the compressibility and the release profile of the hormones which arereleased from the matrix.

The foregoing description and examples have been set forth merely toillustrate the invention and are not intended to be limiting. Sincemodifications of the described embodiments incorporating the spirit andsubstance of the invention may occur to persons skilled in the art, theinvention should be construed broadly to include all variations withinthe scope of the appended claims and equivalents thereof.

1. A pharmaceutical preformulation in the form of a tabletable, solid,free-flowing, dry extract; (a) wherein said solid extract contains auniform amount of a mixture of natural conjugated equine estrogens peramount of support material, defined relative to the main hormoneconstituents; (b) wherein the uniform active-substance content isapplied by spraying an aqueous solution consisting essentially of anextract of said mixture of natural conjugated equine estrogens frompregnant mares' urine onto a powdered or granular pharmaceutical supportmaterial consisting essentially of material selected from the groupconsisting of microcrystalline celluloses and mixtures ofmicrocrystalline cellulose with lactose, and thereafter drying, (c)wherein said preformulation has the active-substance content includingfree estrogens and other solids calculated as dry matter relative to theamount of the pharmaceutical support material in the preformulationlying in the range from 0.25 to 0.70 gram of dry matter per gram ofsupport material; (d) wherein said preformulation has theactive-substance content calculated as the ratio of said mixture ofnatural equine conjugated estrogens relative to the amount of thepharmaceutical support material lying in the range from 35 to 100 mg ofconjugated estrogens per gram of support material; (e) wherein saidpreformulation contains conjugated estrogens in the followingproportions: 52.5 to 61.5% estrone; 22.5 to 30.5% equilin; 13.5 to 19.5%17-α-dihydroequilin; 2.5 to 9.5% estradiol, and 0.5 to 4.0%17-β-dihydroequilin; (f) wherein in said preformulation the proportionof free hormones relative to the total hormone content in the activesubstance is less than 5% by weight; and (g) wherein the preformulationhas a particle-size distribution corresponding to the following sieveanalysis: 100% by weight of the particles pass through a sieve mesh sizeof 500 μm; at least 98% by weight of the particles pass through a sievemesh size of 250 μm; about 65 to 99.5% by weight of the particles passthrough a sieve mesh size of 160 μm; about 35 to 87% by weight of theparticles pass through a sieve mesh size of 125 μm; and fines of lessthan 23% by weight passing through a sieve mesh size of 63 μm.
 2. Apreformulation according to claim 1, wherein said preformulation has theactive substance content lying in the range from 0.28 to 0.64 gram ofdry matter per gram of support material.
 3. A preformulation accordingto claim 1, wherein said preformulation has the active substance contentcalculated as the ratio of said mixture of natural equine conjugatedestrogens relative to the amount of the pharmaceutical support materiallying in the range from 43 to 90 mg of conjugated estrogens per gram ofsupport material.
 4. A preformulation according to claim 1, wherein saidpreformulation has a residual moisture content of at most 3.0% byweight, relative to the entire preformulation as 100% by weight.
 5. Apreformulation according to claim 4, wherein said preformulation has aresidual moisture content of at most 1.0% by weight, relative to theentire preformulation as 100% by weight.
 6. A preformulation accordingto claim 1, wherein the active-substance content, calculated as totalhormone content, lies in the range from about 35 to 100 mg per gram ofthe pharmaceutical support material.
 7. A preformulation according toclaim 6, wherein the active-substance content, calculated as totalhormone content, lies in the range from about 43 to 90 mg per gram ofthe pharmaceutical support material.
 8. A preformulation according toclaim 1, wherein the proportion of free hormones relative to the totalhormone content in the active substance is less than 2% by weight.
 9. Apreformulation according to claim 1, wherein the pharmaceutical supportmaterial is a microcrystalline cellulose or a mixture ofmicrocrystalline celluloses.
 10. A preformulation according to claim 1,wherein the pharmaceutical support material is a mixture ofmicrocrystalline cellulose and lactose.
 11. A preformulation accordingto claim 10, wherein the weight ratio of microcrystalline cellulose tolactose lies in the range of 8:2 to 6:4.
 12. A preformulation accordingto claim 11, wherein the weight ratio of microcrystalline cellulose tolactose lies in the range of about 7.5:2.5 to 6.5:3.5.
 13. Apreformulation according to claim 12, wherein the weight ratio ofmicrocrystalline cellulose to lactose is about 7:3.
 14. A preformulationaccording to claim 1, wherein the mean bulk volume of the preformulationlies in the range from 1.8 to 3.0 ml/g.
 15. A preformulation accordingto claim 1, wherein the mean bulk density of the preformulation lies inthe range from 0.3 to 0.6 grams/ml.
 16. A preformulation according toclaim 1, wherein the preformulation has a particle-size distributioncorresponding to the following sieve analysis: about 0.15% to at most 2%by weight of the particles larger than a mesh size of 250 μm; about 3 to31% by weight of the particles larger than a mesh size of 160 μm; about8 to 36% by weight of the particles larger than a mesh size of 125 μm;and fines of the particles of about 3 to at most 23% by weight passingthrough a sieve mesh size of 63 μm.
 17. A preformulation according toclaim 1, wherein the preformulation has a mean particle size lying inthe range from 50 to 250 μm.
 18. A preformulation according to claim 17,wherein the preformulation has a mean particle size lying in the rangefrom 75 to 150 μm.